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International Journal of COPD 2019:14 13–26

International Journal of COPD

This article was published in the following Dove Press journal:International Journal of COPD

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Open Access Full Text Article

http://dx.doi.org/10.2147/COPD.s157141

emphysema extent on computed tomography is a highly specific index in diagnosing persistent airflow limitation: a real-world study in China

Ting Cheng1–3

Yong li1,3

shuai Pang1

huan Ying Wan1,3

guo Chao shi3,4

Qi Jian Cheng1,3

Qing Yun li3,4

Zi lai Pan5

shao guang huang3,4

1Department of respiratory Medicine, ruijin hospital north, shanghai Jiao Tong University school of Medicine, shanghai, China; 2school of Public health, Fudan University, shanghai, China; 3Institute of respiratory Diseases, shanghai Jiao Tong University school of Medicine, shanghai, China; 4Department of respiratory Medicine, ruijin hospital, shanghai Jiao Tong University school of Medicine, shanghai, China; 5Department of radiology, ruijin hospital north, shanghai Jiao Tong University school of Medicine, shanghai, China

Objective: The diagnostic value of emphysema extent in consistent air flow limitation remains

controversial. Therefore, we aimed to assess the value of emphysema extent on computed

tomography (CT) on the diagnosis of persistent airflow limitation. Furthermore, we developed

a diagnostic criterion for further verification.

Materials and methods: We retrospectively enrolled patients who underwent chest CT and

lung function test. To be specific, 671 patients were enrolled in the derivation group (Group 1.1),

while 479 patients were in the internal validation group (Group 1.2). The percentage of lung

volume occupied by low attenuation areas (LAA%) and the percentile of the histogram of

attenuation values were calculated.

Results: In patients with persistent airflow limitation, the LAA% was higher and the percentile

of the histogram of attenuation values was lower, compared with patients without persistent

airflow limitation. Using LAA% with a threshold of -950 HU .1.4% as the criterion, the

sensitivity was 44.3% and 47.2%, and the specificity was 95.2% and 95.7%, in Group 1.1 and

Group 1.2, respectively. The specificity was influenced by the coexistence of interstitial lung

disease, pneumothorax, and post-surgery, rather than the coexistence of pneumonia, nodule, or

mass. Multivariable models were also developed.

Conclusion: The emphysema extent on CT is a highly specific marker in the diagnosis of

persistent airflow limitation.

Keywords: computed tomography, lung function test, emphysema, persistent airflow

limitation

IntroductionCOPD is characterized by persistent airflow limitation, which is usually progressive

and associated with an enhanced chronic inflammatory response to noxious particles or

gases.1 In the US, COPD is the fourth leading cause of morbidity and mortality, while

its burden is estimated to be the fifth in 2020 worldwide.1,2 COPD is a preventable and

treatable disease, and the effective treatment of COPD relies on accurate diagnosis

and assessment. Thus, using different methods to facilitate the diagnosis of COPD and

evaluate the severity of the disease accurately is of great significance.

According to the current diagnostic criteria of COPD, persistent airflow limitation

in spirometry is indispensable. The ratio of post-bronchodilator forced expiratory

volume in 1 second (FEV1) to forced vital capacity (FVC) ,0.70 confirms persistent

airflow limitation.1 However, in clinical practice, some patients are not able to take

the spirometry examination. Patients with dysaudia or other hearing disorders tend to

get unsatisfactory spirometry results.3,4 Furthermore, patients with severe emphysema

Correspondence: huan Ying WanDepartment of respiratory Medicine, ruijin hospital north, shanghai Jiao Tong University school of Medicine, no 999, Xiwang road, Malu Town, Jiading, shanghai 201801, ChinaTel +86 1 812 126 3363Fax +86 0 216 788 8855email hy_wan2013@163.com

guo Chao shiDepartment of respiratory Medicine, ruijin hospital, shanghai Jiao Tong University school of Medicine, no 197, ruijin er road, huangpu District, shanghai 200025, Chinaemail shiguochao@hotmail.com

Journal name: International Journal of COPDArticle Designation: Original ResearchYear: 2019Volume: 14Running head verso: Cheng et alRunning head recto: Diagnosing COPD using emphysema extent on CTDOI: 157141

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are not recommended to do spirometry for the high risk of

pneumothorax.5 In addition, spirometry could detect and

monitor the fluctuation of airflow limitation such as COPD

exacerbation sensitively.6,7 Therefore, spirometry during

COPD exacerbation may not reflect the baseline lung func-

tion accurately.

Computed tomography (CT) is widely used in the diagno-

sis of lung disease. It is sensitive and accurate enough to help

with the diagnosis of lung infections, pneumonia, bronchiecta-

sis, interstitial lung disease, and pleural effusion. The airflow

limitation is due to several pathological structural changes in

the lung, such as lung parenchyma destruction (or emphysema)

and small airway disease.8 Chest CT can be used to assess the

severity of emphysema correctly.9 The main index of emphy-

sema extent on CT includes the percentage of the lung volume

occupied by low attenuation areas (LAA%) and percentile

of the histogram of attenuation values (Perc n).10 Mohamed

Hoesein et al11 had suggested that the emphysema extents on

CT in patients with airflow limitation was significantly higher

than in those without airflow limitation. Moreover, the change

of emphysema extent on CT can predict mortality in COPD

patients.12 In addition, Mets et al had successfully identified

airflow limitation using CT images in participants in a lung

cancer screening trial.13 A meta-analysis systemically analyzed

the diagnostic value of CT for COPD and concluded that CT

might be useful in identifying the potential suspected patients

with COPD.14 However, in previous studies, the sample sizes

of these studies were relatively small. Besides, in the biggest

study of Mets et al, bronchial dilation test was not performed

and subjects were not from Asia.15

In the present study, we evaluated the efficacy of emphy-

sema extent on CT in diagnosing persistent airflow limitation

in China and tried to develop diagnostic criteria for further

verification.

Materials and methodsstudy populationThis was a retrospective cross sectional study, which was

performed in Shanghai Ruijin Hospital in China. Patients who

underwent chest CT and lung function test from January 2010

to June 2014 were retrospectively enrolled in the study and

divided to four groups (groups 1–4). The results of chest CT

and lung function tests were recorded. The inclusion criteria

of each group were as follows.

The inclusion criteria for Group 1 were 1) patients who

underwent lung function test together with a bronchodila-

tion test and 2) CT images reconstructed using a standard

(or B26, B30, B31, B41, I30, I31, I41) algorithm, a section

thickness of 5 mm, and an interval of 5 mm. Patients who had

interstitial lung disease, pneumothorax, and/or post-thoracic

surgery were excluded. The patients in Group 1 were further

randomly divided into two groups, including a derivation

group (Group 1.1) with 60% of the patients and an internal

validation group (Group 1.2) with the remaining 40%.

The inclusion criteria for Group 2 were 1) patients who

underwent lung function test without a bronchodilation test

and 2) CT images reconstructed using a standard (or B26,

B30, B31, B41, I30, I31, I41) algorithm, a section thick-

ness of 5 mm, and an interval of 5 mm. Patients who had

interstitial lung disease, pneumothorax, and/or post-thoracic

surgery were excluded.

The inclusion criteria for Group 3 were 1) patients who

underwent lung function test with a bronchodilation test and

2) CT images reconstructed using other parameters (mostly

a standard algorithm and a section thickness of 7.5 mm).

Patients who had interstitial lung disease, pneumothorax,

and/or post-thoracic surgery were excluded.

The inclusion criteria for Group 4 were 1) patients who

underwent lung function test with a bronchodilation test;

2) CT images reconstructed using a standard (or B26, B30,

B31, B41, I30, I31, I41) algorithm, a section thickness of

5 mm, and an interval of 5 mm and 3) patients who had CT

manifestation of other diseases. Group 4 was further divided

into seven subgroups. Group 4.1 included patients with lung

infiltration on chest CT. Group 4.2 included patients with CT

manifestation of bronchiectasis. Group 4.3 included patients

with a lung mass on chest CT. Group 4.4 included patients

with a lung nodule on chest CT. Group 4.5 included

patients with interstitial lung disease reflected on CT. Group

4.6 included patients with pneumothorax, while Group 4.7

included patients who had undergone thoracic surgeries.

The present study was approved by the Ruijin North

Hospital Ethics Committee.

CT scanning and analysisChest CT was performed according to the standardization

protocols by using one of the five following CT scanners:

Discovery CT750 HD (GE Medical Systems, Milwaukee,

WI, USA), LightSpeed VCT (GE Medical Systems), Light-

Speed16 (GE Medical Systems), Perspective (Siemens

Medical Solutions, Forchheim, Germany), and SOMATOM

Definition Flash (Siemens Medical Solutions). The following

technical parameters were used: tube voltage, 100–140 kVp;

tube current, 100–250 mA; tube rotation time, 0.8 seconds;

single collimation width, 1.25 mm; total collimation width,

20 mm; table speed, 23 or 34 mm per rotation; table feed

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Diagnosing COPD using emphysema extent on CT

per rotation, 18.75 or 27.5; and spiral pitch factor, 0.9375

or 1.375. Images were reconstructed using a standard, bone,

boneplus, lung, or B26, B30, B31, B41, B50, B70, B75,

B80, I30, I31, I41, I50, I80 algorithm, a section thickness

of 1.25–10 mm, an interval similar to the section thickness,

and a 512×512 matrix.

The LAA% was calculated automatically using the

commercial software Myrian® (Intrasense, Montpellier,

France) under every threshold from -1,020 to -201 HU with

an interval of 1 HU. Every Perc n was further calculated

(Perc 1–Perc 99 with an interval of 1%).

lung function testThe lung function test (spirometry and single-breath deter-

mination of carbon monoxide uptake), including reversibility

tests, was performed using Jaeger® MasterScreen Body/Diff

system (CareFusion Corporation, San Diego, CA, USA)

according to the American Thoracic Society/European

Respiratory guidelines. The single-breath determination of

carbon monoxide uptake in the lung was used to calculate the

diffusing capacity and lung volume. A post-bronchodilator

FEV1 to FVC ratio ,70% was defined as the persistent

airflow limitation.

statistical analysisDescriptive statistics included frequency tables, median and

interquartile range (for the data without normal distribution),

and mean and SD (for the data with normal distribution).

The emphysema extents (LAA% of every threshold and

every percentile [Perc] of the histogram) were compared in

Group 1 between patients with and without persistent airflow

limitation using Mann–Whitney U test.

The LAA% using thresholds ranging from -1,000

to -850 HU with an interval of 5 HU and Perc 1, Perc 3,

Perc 5, Perc 6, Perc 9, Perc 12, Perc 15, Perc 18, and Perc 21

were included for the diagnostic efficiency evaluation. The

areas under the receiver-operating characteristic (ROC) curve

(AUCs) for LAA% and Perc n were calculated in diagnosing

persistent airflow limitation in Group 1.1 (derivation group).

The cut points were chosen where the highest Youden index

was observed, and where the specificity equaled to 90%, 95%,

and 99% in Group 1.1. The sensitivity, specificity, and positive

and negative predictive values (PPV and NPV, respectively)

were calculated for every cut point mentioned above using

data from Group 1.1 (derivation group), Group 1.2 (internal

validation group), and Groups 2, respectively. The AUC was

also measured in diagnosing persistent airflow limitation in

Group 1.2. The cut points were chosen as mentioned above.

Binary logistic regressions were performed to examine

the factors for predicting persistent airflow limitation.

Common index of emphysema extent (LAA% [-950 HU])

and demographic characteristics of the patients (age, sex,

height, and weight) were included in Model 1. Model 2

included LAA% (-950 HU), Perc 15, and the demographic

characteristics. Model 3 included LAA% (-950 HU),

LAA% under the threshold where the AUC was the highest,

Perc 15, the percentile where the AUC was the highest, and

the demographic characteristics. LAA% under every

threshold, every percentile (Perc 1–Perc 99), and the

demographic characteristics were included in Model 4.

The AUCs for different models were calculated and the

cut points were chosen as above. The sensitivity, speci-

ficity, PPV, and NPV were calculated for every cut point

in Group 1.1 and Group 1.2. The ROC curve of different

models and emphysema extent index were compared using

Z test. All statistical analyses were conducted using SPSS

17.0 (SPSS Inc., Chicago, IL, USA).

Informed consentThe present study was approved by the Ruijin North Hospital

Ethics Committee, and the requirement to obtain informed

written consent was waived. The reasons are as follows:

1) no foreseeable harm is expected to result from this study

and less than minimal risk; 2) the waiver of informed con-

sent will not affect the health and rights of the subjects; and

3) patient data confidentiality was protected. Statement:

Informed consent was waived by the Ruijin North Hospital

Ethics Committee.

ResultsPopulation characteristicsA total of 2,976 patients who underwent chest CT and

lung function test from January 2010 to June 2014 were

enrolled. After excluding 435 patients with interstitial

lung disease, pneumothorax, or post-thoracic surgery and

141 patients whose CT images were reconstructed using

other para meters, 2,400 patients (CT images were recon-

structed using a standard algorithm and a section thickness

of 5 mm) were included in Group 1 and Group 2. Among

these 2,400 patients, 1,250 patients did not undergo broncho-

dilation tests (Group 2, the external validation group), while

1,150 patients did (Group 1). Therefore, 671 patients were

randomly assigned to Group 1.1 (the derivation group) and

479 to Group 1.2 (the internal validation group). The flow

chart is illustrated in Figure 1. The demographic features

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Cheng et al

of Group 1.1, Group 1.2, and Group 2 are summarized in

Table 1. The demographic features for Group 3 and Group 4

are available in Table S1.

Comparison of the emphysema extent between patients with and without persistent airflow limitationThe emphysema extent of patients in Group 1 (including

groups 1.1 and 1.2) is shown in Figure 2. The emphysema

index of patients with persistent airflow limitation was sig-

nificantly higher than that of those without persistent airflow

limitation (P,0.01). LAA% (-950 HU) was significantly

different between patients with and without persistent airflow

limitation for patients in different genders and different age

groups between 40 and 90 years.

The correlation between post-bronchodilator FEV1/

FVC and emphysema extent is shown in Figure 3.

Post-bronchodilator FEV1/FVC was negatively correlated with

LAA% with the threshold of -950 HU (group 1.1: r=-0.355;

group 1.2: r=-0.320) and positively correlated with Perc 15

(group 1.1: r=0.306; group 1.2: r=0.377).

The diagnostic value of emphysema extent in diagnosing persistent airflow limitationThe AUCs of different emphysema indexes in diagnosing

persistent airflow limitation are shown in Figure 4. The

max AUC of LAA% was 0.83 (SD 0.02) with the threshold

of -930 HU, while the AUC with the threshold of -950 HU

was 0.79 (SD 0.02). The max AUC of Perc n was 0.83 (SD

0.02) in Perc 3, while the AUC of Perc 15 was 0.78 (SD

0.02). However, no significant difference was observed in

AUC between LAA% (-930 HU) and LAA% (-950 HU),

as well as between Perc 15 and Perc 3.

The diagnostic value of emphysema extent in diag-

nosing persistent airflow limitation using different cut

points is summarized in Part A in Table 2. Using LAA%

(-950 HU) .1.4% as the criterion, the sensitivity was 44.3%

Figure 1 The flow chart of patient selection.Abbreviation: CT, computed tomography.

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Diagnosing COPD using emphysema extent on CT

and 47.2%, while the specificity was 95.2% and 95.7% in

Group 1.1 and Group 1.2, respectively.

In patients who did not undergo the bronchodilation test,

the emphysema extent was also a highly specific index in

diagnosing airflow limitation (Table 2 Part B). Using LAA%

(threshold of -950 HU) .1.4% as the criterion, the sensitivity

in Group 2 was 38.3%, while the specificity was 94.9%.

On CT reconstructed by a section thickness of 7.5 mm, the

emphysema extent using the same cut point showed similar

specificity and a slightly lower sensitivity in diagnosing

persistent airflow limitation in Group 3 (Table 2 Part C).

The diagnostic value of emphysema extent in diagnosing persistent airflow limitation in patients with other lung diseasesThe diagnostic value of emphysema extent in diagnosing

persistent airflow limitation in patients with other lung dis-

eases in Group 4 is shown in Part D in Table 2. Using LAA%

(threshold of -950 HU) .1.4% as the criterion, the specific-

ity was still above 95% in patients with lung infiltration, as

well as mass and nodule in lungs, 92.9% in patients with

bronchiectasis, and lower than 90% in patients with intersti-

tial lung disease, pneumothorax, or post-thoracic surgery.

Multivariable model based on emphysema extent for diagnosing persistent airflow limitationFour models were established by logistic regressions. The

independent predictors of persistent airflow limitation are

summarized in Table S2. The models are as follows.

Model 1: y1 = 0.792 × LAA% (-950 HU) + 0.026 × age

(years) + 0.608 × sex (male = 1, female = 0) - 3.503

Model 2: y2 = 0.68 × LAA% (-950 HU) - 0.017 × Perc 15

+ 0.029 × age (years) + 0.023 × wt (kg) - 20.132

Model 3: y3 = 0.168 × LAA% (-930 HU) - 0.064 × Perc 3

+ 0.039 × Perc 15 + 0.026 × age (years) - 27.515

Model 4: y4 = 0.218 × Perc 4 - 0.554 × Perc 8 + 0.614 × Perc 33 - 0.321 × Perc 43 + 0.042 × Perc 97 - 0.304 × LAA% (-973 HU) + 0.187 × LAA% (-927 HU) + 1.633

× LAA% (-292 HU) - 190.496

P (persistent airflow limitation) = e^y/(1 + e^y)

Table 1 Demographic features of the derivation, internal validation, and external validation groups

Group 1.1 (derivation) Group 1.2 (internal validation) Group 2 (external validation)

number 671 479 1,250Male 347 (51.7) 255 (53.2) 644 (51.5)age (years) 59 (50–65) 59 (51–65) 61 (53–69)height (cm) 165 (160–171) 165 (160–171) 165 (158–171)Weight (kg) 63 (55–71) 65 (58–72) 62 (55–70)BMI (kg/m2) 23.4±3.4 23.6±3.6 23.2±3.4FVC (l) 2.71 (2.19–3.32) 2.70 (2.23–3.35) 2.49 (1.98–3.14)FeV1 (l) 2.18 (1.63–2.70) 2.11 (1.61–2.69) 2.04 (1.62–2.60)FeV1/FVC (%) 82.1 (72.2–89.5) 81.1 (69.6–89.7) 84.3 (76.5–91.3)rV/TlC (%) 46.7±9.2 47.2±9.1 46.5±8.4TLC-SB 4.60±0.99 4.63±1.02 4.46±0.99DlCO sB 5.44±1.88 5.46±1.89 5.12±1.77DlCO/Va 1.29 (1.08–1.46) 1.28 (1.06–1.48) 1.21 (1.01–1.40)FeV1% pred 85.1 (66.4–97.5) 84.7 (65.0–96.3) 83.4 (67.9–95.7)FVC% pred 83.4±17.5 83.0±17.3 80.3±17.5TLC-SB% pred 79.9±12.1 79.9±12.3 79.1±12.2DlCO sB% pred 67.3±17.3 66.4±18.7 63.0±17.5DlCO/Va% pred 87.8 (76.2–99.2) 88.7 (75.1–99.5) 82.0 (70.7–93.4)FeV1 (L) post-bronchodilation 2.31±0.86 2.27±0.81 naFeV1/FVC (%) post-bronchodilation 84.1 (73.9–91.0) 83.2 (72.0–90.2) naFeV1%pred post-bronchodilation 89.1 (72.2–100.5) 87.5 (70.8–99.2) naFeV1/FVC ,70% post-bronchodilation 131 (19.5) 106 (22.1) naFeV1/FVC ,70% 147 (21.9) 117 (24.4) 180 (14.4)Positive in bronchodilation test 87 (13) 63 (13.2) nalaa% (-950 hU) 0.30 (0.07–0.69) 0.30 (0.05–0.73) 0.24 (0.06–0.55)Perc 15 (hU) -889 (-906 to -868) -889 (-906 to -867) -875 (-896 to -849)

Abbreviations: BMI, body mass index; DlCO, diffusion capacity for carbon monoxide of the lung; FeV1, forced expiratory volume in 1 second; FVC, forced vital capacity; laa%, percentage of the lung volume occupied by low attenuation areas; Perc n, percentile of the histogram of attenuation values; rV, residual volume; TlC, total lung capacity; TLC-SB, the single-breath diffusing capacity of the lung for CO; DLCO SB, diffusion capacity for carbon monoxide of the lung, using single-breath method; DLCO/Va, diffusion capacity for carbon monoxide of the lung per liters of alveolar.

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Figure 2 The emphysema extent of patients in group 1 (including derivation group and internal validation group).Notes: (A) laa%; (B) Perc n.Abbreviations: laa%, percentage of the lung volume occupied by low attenuation areas; Perc n, percentile of the histogram of attenuation values.

Figure 3 The correlation between post-bronchodilator FEV1/FVC and emphysema extent.Notes: (A) laa% using the threshold of -950 hU; (B) Perc 15 (hU).Abbreviations: FeV1, forced expiratory volume in 1 second; FVC, forced vital capacity; laa%, percentage of the lung volume occupied by low attenuation areas; Perc n, percentile of the histogram of attenuation values.

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Diagnosing COPD using emphysema extent on CT

Figure 4 The AUCs of different emphysema indexes in diagnosing persistent airflow limitation.Notes: (A) laa% using different thresholds (hU); (B) Perc n.Abbreviations: aUC, area under the rOC curve; laa%, percentage of the lung volume occupied by low attenuation areas; Perc n, percentile of the histogram of attenuation values; ROC, receiver-operating characteristic.

Table 2 Diagnostic values of the emphysema extent in diagnosing persistent airflow limitation using different cut point in groups 1–4

Rule A B C D Sensitivity (%) Specificity (%) PPV (%) NPV (%) Kappa

A: Group 1laa% (-950 hU) .0.84%

group 1.1 77 63 54 477 58.8 88.3 55.0 89.8 0.83group 1.2 65 45 41 328 61.3 87.9 59.1 88.9 0.82

laa% (-950 hU) .0.90%group 1.1 73 53 58 487 55.7 90.2 57.9 89.4 0.83group 1.2 62 39 44 334 58.5 89.5 61.4 88.4 0.83

laa% (-950 hU) .1.4%group 1.1 58 26 73 514 44.3 95.2 69.0 87.6 0.85group 1.2 50 16 56 357 47.2 95.7 75.8 86.4 0.85

laa% (-950 hU) .3.0%group 1.1 43 5 88 535 32.8 99.1 89.6 85.9 0.86group 1.2 33 4 73 369 31.1 98.9 89.2 83.5 0.84

Perc 15 ,-907 hUgroup 1.1 73 76 58 464 55.7 85.9 49.0 88.9 0.8group 1.2 63 52 43 321 59.4 86.1 54.8 88.2 0.8

Perc 15 ,-910 hUgroup 1.1 63 53 68 487 48.1 90.2 54.3 87.7 0.82group 1.2 60 32 46 341 56.6 91.4 65.2 88.1 0.84

Perc 15 ,-915 hUgroup 1.1 54 23 77 517 41.2 95.7 70.1 87.0 0.85group 1.2 49 19 57 354 46.2 94.9 72.1 86.1 0.84

Perc 15 ,-928 hUgroup 1.1 33 4 98 536 25.2 99.3 89.2 84.5 0.85group 1.2 24 0 82 373 22.6 100.0 100.0 82.0 0.83

laa% (-930 hU) .1.4%group 1.1 103 142 28 398 78.6 73.7 42.0 93.4 0.75group 1.2 86 97 20 276 81.1 74.0 47.0 93.2 0.76

laa% (-930 hU) .3.4%group 1.1 76 53 55 487 58.0 90.2 58.9 89.9 0.84group 1.2 72 34 34 339 67.9 90.9 67.9 90.9 0.86

laa% (-930 hU) .5.2%group 1.1 65 26 66 514 49.6 95.2 71.4 88.6 0.86group 1.2 56 20 50 353 52.8 94.6 73.7 87.6 0.85

laa% (-930 hU) .13%group 1.1 38 5 93 535 29.0 99.1 88.4 85.2 0.85group 1.2 25 1 81 372 23.6 99.7 96.2 82.1 0.83

(Continued)

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Table 2 (Continued)

Rule A B C D Sensitivity (%) Specificity (%) PPV (%) NPV (%) Kappa

Perc 3 ,-922 hUgroup 1.1 96 124 35 416 73.3 77.0 43.6 92.2 0.76group 1.2 85 78 21 295 80.2 79.1 52.1 93.4 0.79

Perc 3 ,-931 hUgroup 1.1 75 52 56 488 57.3 90.4 59.1 89.7 0.84group 1.2 70 32 36 341 66.0 91.4 68.6 90.5 0.86

Perc 3 ,-937 hUgroup 1.1 64 24 67 516 48.9 95.6 72.7 88.5 0.86group 1.2 54 16 52 357 50.9 95.7 77.1 87.3 0.86

Perc 3 ,-951 hUgroup 1.1 39 4 92 536 29.8 99.3 90.7 85.4 0.86group 1.2 28 4 78 369 26.4 98.9 87.5 82.6 0.83

B: Group 2laa% (-950 hU) .0.84% 86 113 94 957 47.8 89.4 43.2 91.1 0.83laa% (-950 hU) .0.90% 83 99 97 971 46.1 90.7 45.6 90.9 0.84laa% (-950 hU) .1.4% 69 55 111 1,015 38.3 94.9 55.6 90.1 0.87laa% (-950 hU) .3.0% 44 11 136 1,059 24.4 99.0 80.0 88.6 0.88Perc 15 ,-907 hU 77 84 103 986 42.8 92.1 47.8 90.5 0.85Perc 15 ,-910 hU 73 61 107 1,009 40.6 94.3 54.5 90.4 0.87Perc 15 ,-915 hU 64 37 116 1,033 35.6 96.5 63.4 89.9 0.88Perc 15 ,-928 hU 35 4 145 1,066 19.4 99.6 89.7 88.0 0.88laa% (-930 hU) .1.4% 112 215 68 855 62.2 79.9 34.3 92.6 0.77laa% (-930 hU) .3.4% 86 77 94 993 47.8 92.8 52.8 91.4 0.86laa% (-930 hU) .5.2% 75 40 105 1,030 41.7 96.3 65.2 90.7 0.88laa% (-930 hU) .13% 39 5 141 1,065 21.7 99.5 88.6 88.3 0.88Perc 3 ,-922 hU 108 165 72 905 60.0 84.6 39.6 92.6 0.81Perc 3 ,-931 hU 85 72 95 998 47.2 93.3 54.1 91.3 0.87Perc 3 ,-937 hU 70 38 110 1,032 38.9 96.4 64.8 90.4 0.88Perc 3 ,-951 hU 44 10 136 1,060 24.4 99.1 81.5 88.6 0.88C: Group 3laa% (-950 hU) .0.84% 2 3 3 32 40.0 91.4 40.0 91.4 0.85laa% (-950 hU) .0.90% 2 3 3 32 40.0 91.4 40.0 91.4 0.85laa% (-950 hU) .1.4% 2 2 3 33 40.0 94.3 50.0 91.7 0.88laa% (-950 hU) .3.0% 1 0 4 35 20.0 100.0 100.0 89.7 0.90Perc 15 ,-907 hU 2 1 3 34 40.0 97.1 66.7 91.9 0.90Perc 15 ,-910 hU 2 1 3 34 40.0 97.1 66.7 91.9 0.90Perc 15 ,-915 hU 2 0 3 35 40.0 100.0 100.0 92.1 0.93Perc 15 ,-928 hU 0 0 5 35 0.0 100.0 na 87.5 0.88laa% (-930 hU) .1.4% 2 6 3 29 40.0 82.9 25.0 90.6 0.78laa% (-930 hU) .3.4% 2 2 3 33 40.0 94.3 50.0 91.7 0.88laa% (-930 hU) .5.2% 2 1 3 34 40.0 97.1 66.7 91.9 0.90laa% (-930 hU) .13% 0 0 5 35 0.0 100.0 na 87.5 0.88Perc 3 ,-922 hU 2 4 3 31 40.0 88.6 33.3 91.2 0.83Perc 3 ,-931 hU 2 2 3 33 40.0 94.3 50.0 91.7 0.88Perc 3 ,-937 hU 2 1 3 34 40.0 97.1 66.7 91.9 0.90Perc 3 ,-951 hU 1 0 4 35 20.0 100.0 100.0 89.7 0.90D: Group 4laa% (-950 hU) .0.84%

With lung infiltration 48 38 40 233 54.5 86.0 55.8 85.3 0.78With bronchiectasis 19 8 7 34 73.1 81.0 70.4 82.9 0.78With mass in lung 11 10 4 52 73.3 83.9 52.4 92.9 0.82With nodule in lung 78 56 55 470 58.6 89.4 58.2 89.5 0.83With interstitial lung disease 18 14 4 49 81.8 77.8 56.3 92.5 0.79With pneumothorax 1 1 0 5 100 83.3 50.0 100 0.86Post-thoracic surgery 1 7 5 21 16.7 75.0 12.5 80.8 0.65

(Continued)

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Diagnosing COPD using emphysema extent on CT

Table 2 (Continued)

Rule A B C D Sensitivity (%) Specificity (%) PPV (%) NPV (%) Kappa

laa% (-950 hU) .0.90%With lung infiltration 45 32 43 239 51.1 88.2 58.4 84.8 0.79With bronchiectasis 19 8 7 34 73.1 81.0 70.4 82.9 0.78With mass in lung 10 7 5 55 66.7 88.7 58.8 91.7 0.84With nodule in lung 76 47 57 479 57.1 91.1 61.8 89.4 0.84With interstitial lung disease 17 12 5 51 77.3 81.0 58.6 91.1 0.80With pneumothorax 1 1 0 5 100 83.3 50.0 100 0.86Post-thoracic surgery 1 6 5 22 16.7 78.6 14.3 81.5 0.68

laa% (-950 hU) .1.4%With lung infiltration 33 9 55 262 37.5 96.7 78.6 82.6 0.82With bronchiectasis 14 3 12 39 53.8 92.9 82.4 76.5 0.78With mass in lung 8 2 7 60 53.3 96.8 80.0 89.6 0.88With nodule in lung 65 24 68 502 48.9 95.4 73.0 88.1 0.86With interstitial lung disease 17 9 5 54 77.3 85.7 65.4 91.5 0.84With pneumothorax 1 1 0 5 100 83.3 50.0 100 0.86Post-thoracic surgery 0 4 6 24 0.0 85.7 0.0 80.0 0.71

laa% (-950 hU) .3.0%With lung infiltration 22 2 66 269 25.0 99.3 91.7 80.3 0.81With bronchiectasis 10 1 16 41 38.5 97.6 90.9 71.9 0.75With mass in lung 5 0 10 62 33.3 100 100 86.1 0.87With nodule in lung 40 5 93 521 30.1 99.0 88.9 84.9 0.85With interstitial lung disease 16 4 6 59 72.7 93.7 80.0 90.8 0.88With pneumothorax 0 0 1 6 0.0 100 na 85.7 0.86Post-thoracic surgery 0 3 6 25 0.0 89.3 0.0 80.6 0.74

Perc 15 ,-907 hUWith lung infiltration 43 40 45 231 48.9 85.2 51.8 83.7 0.76With bronchiectasis 17 9 9 33 65.4 78.6 65.4 78.6 0.74With mass in lung 7 5 8 57 46.7 91.9 58.3 87.7 0.83With nodule in lung 79 68 54 458 59.4 87.1 53.7 89.5 0.81With interstitial lung disease 14 5 8 58 63.6 92.1 73.7 87.9 0.85With pneumothorax 0 2 1 4 0.0 66.7 0.0 80.0 0.57Post-thoracic surgery 0 3 6 25 0.0 89.3 0.0 80.6 0.74

Perc 15 ,-910 hUWith lung infiltration 37 25 51 246 42.0 90.8 59.7 82.8 0.79With bronchiectasis 15 4 11 38 57.7 90.5 78.9 77.6 0.78With mass in lung 6 1 9 61 40.0 98.4 85.7 87.1 0.87With nodule in lung 71 49 62 477 53.4 90.7 59.2 88.5 0.83With interstitial lung disease 14 4 8 59 63.6 93.7 77.8 88.1 0.86With pneumothorax 0 0 1 6 0.0 100 na 85.7 0.86Post-thoracic surgery 0 3 6 25 0.0 89.3 0.0 80.6 0.74

Perc 15 ,-915 hUWith lung infiltration 28 16 60 255 31.8 94.1 63.6 81.0 0.79With bronchiectasis 12 2 14 40 46.2 95.2 85.7 74.1 0.76With mass in lung 6 1 9 61 40.0 98.4 85.7 87.1 0.87With nodule in lung 55 22 78 504 41.4 95.8 71.4 86.6 0.85With interstitial lung disease 14 2 8 61 63.6 96.8 87.5 88.4 0.88With pneumothorax 0 0 1 6 0.0 100 na 85.7 0.86Post-thoracic surgery 0 2 6 26 0.0 92.9 0.0 81.3 0.76

Perc 15 ,-928 hUWith lung infiltration 19 1 69 270 21.6 99.6 95.0 79.6 0.81With bronchiectasis 8 1 18 41 30.8 97.6 88.9 69.5 0.72With mass in lung 5 0 10 62 33.3 100 100 86.1 0.87With nodule in lung 34 5 99 521 25.6 99.0 87.2 84.0 0.84With interstitial lung disease 15 4 7 59 68.2 93.7 78.9 89.4 0.87With pneumothorax 0 0 1 6 0.0 100 na 85.7 0.86Post-thoracic surgery 0 3 6 25 0.0 89.3 0.0 80.6 0.74

(Continued)

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Table 2 (Continued)

Rule A B C D Sensitivity (%) Specificity (%) PPV (%) NPV (%) Kappa

laa% (-930 hU) .1.4%With lung infiltration 64 78 24 193 72.7 71.2 45.1 88.9 0.72With bronchiectasis 23 17 3 25 88.5 59.5 57.5 89.3 0.71With mass in lung 11 15 4 47 73.3 75.8 42.3 92.2 0.75With nodule in lung 109 132 24 394 82.0 74.9 45.2 94.3 0.76With interstitial lung disease 18 18 4 45 81.8 71.4 50.0 91.8 0.74With pneumothorax 1 2 0 4 100 66.7 33.3 100 0.71Post-thoracic surgery 2 7 4 21 33.3 75.0 22.2 84.0 0.68

laa% (-930 hU) .3.4%With lung infiltration 49 28 39 243 55.7 89.7 63.6 86.2 0.81With bronchiectasis 17 8 9 34 65.4 81.0 68.0 79.1 0.75With mass in lung 10 4 5 58 66.7 93.5 71.4 92.1 0.88With nodule in lung 85 53 48 473 63.9 89.9 61.6 90.8 0.85With interstitial lung disease 17 11 5 52 77.3 82.5 60.7 91.2 0.81With pneumothorax 1 1 0 5 100 83.3 50.0 100 0.86Post-thoracic surgery 1 6 5 22 16.7 78.6 14.3 81.5 0.68

laa% (-930 hU) .5.2%With lung infiltration 38 17 50 254 43.2 93.7 69.1 83.6 0.81With bronchiectasis 16 4 10 38 61.5 90.5 80.0 79.2 0.79With mass in lung 6 1 9 61 40.0 98.4 85.7 87.1 0.87With nodule in lung 71 24 62 502 53.4 95.4 74.7 89.0 0.87With interstitial lung disease 16 5 6 58 72.7 92.1 76.2 90.6 0.87With pneumothorax 0 0 1 6 0.0 100 na 85.7 0.86Post-thoracic surgery 0 3 6 25 0.0 89.3 0.0 80.6 0.74

laa% (-930 hU) .13%With lung infiltration 19 1 69 270 21.6 99.6 95.0 79.6 0.81With bronchiectasis 9 0 17 42 34.6 100 100 71.2 0.75With mass in lung 5 1 10 61 33.3 98.4 83.3 85.9 0.86With nodule in lung 35 3 98 523 26.3 99.4 92.1 84.2 0.85With interstitial lung disease 10 1 12 62 45.5 98.4 90.9 83.8 0.85With pneumothorax 0 0 1 6 0.0 100 na 85.7 0.86Post-thoracic surgery 0 1 6 27 0.0 96.4 0.0 81.8 0.79

Perc 3 ,-922 hUWith lung infiltration 60 59 28 212 68.2 78.2 50.4 88.3 0.76With bronchiectasis 21 15 5 27 80.8 64.3 58.3 84.4 0.71With mass in lung 11 12 4 50 73.3 80.6 47.8 92.6 0.79With nodule in lung 103 114 30 412 77.4 78.3 47.5 93.2 0.78With interstitial lung disease 17 16 5 47 77.3 74.6 51.5 90.4 0.75With pneumothorax 1 2 0 4 100 66.7 33.3 100 0.71Post-thoracic surgery 1 8 5 20 16.7 71.4 11.1 80.0 0.62

Perc 3 ,-931 hUWith lung infiltration 47 28 41 243 53.4 89.7 62.7 85.6 0.81With bronchiectasis 17 8 9 34 65.4 81.0 68.0 79.1 0.75With mass in lung 10 3 5 59 66.7 95.2 76.9 92.2 0.90With nodule in lung 82 51 51 475 61.7 90.3 61.7 90.3 0.85With interstitial lung disease 17 10 5 53 77.3 84.1 63.0 91.4 0.82With pneumothorax 1 1 0 5 100 83.3 50.0 100 0.86Post-thoracic surgery 1 5 5 23 16.7 82.1 16.7 82.1 0.71

Perc 3 ,-937 hUWith lung infiltration 18 0 70 271 20.5 100 100 79.5 0.81With bronchiectasis 9 0 17 42 34.6 100 100 71.2 0.75With mass in lung 4 0 11 62 26.7 100 100 84.9 0.86With nodule in lung 32 2 101 524 24.1 99.6 94.1 83.8 0.84With interstitial lung disease 10 1 12 62 45.5 98.4 90.9 83.8 0.85With pneumothorax 0 0 1 6 0.0 100 na 85.7 0.86Post-thoracic surgery 0 1 6 27 0.0 96.4 0.0 81.8 0.79

(Continued)

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Diagnosing COPD using emphysema extent on CT

Table 2 (Continued)

Rule A B C D Sensitivity (%) Specificity (%) PPV (%) NPV (%) Kappa

Perc 3 ,-951 hUWith lung infiltration 38 15 50 256 43.2 94.5 71.7 83.7 0.82With bronchiectasis 16 4 10 38 61.5 90.5 80.0 79.2 0.79With mass in lung 7 1 8 61 46.7 98.4 87.5 88.4 0.88With nodule in lung 72 25 61 501 54.1 95.2 74.2 89.1 0.87With interstitial lung disease 17 5 5 58 77.3 92.1 77.3 92.1 0.88With pneumothorax 0 0 1 6 0.0 100 na 85.7 0.86Post-thoracic surgery 0 3 6 25 0.0 89.3 0.0 80.6 0.74

Notes: A, true positives (with obvious emphysema and persistent airflow limitation); B, false positives (with obvious emphysema, but without persistent airflow limitation); C, false negatives (without obvious emphysema, but with persistent airflow limitation); D, true negatives (without obvious emphysema and persistent airflow limitation).Abbreviations: laa%, percentage of the lung volume occupied by low attenuation areas; nPV, negative predictive value; Perc n, percentile of the histogram of attenuation values; PPV, positive predictive value.

Model 4 showed the best discrimination in both Group 1.1

and Group 1.2. The discrimination in Group 1.1 was Model

4.Model 3.LAA% (-930 HU).Perc 3.Model 2.Model

1.LAA% (-950 HU).Perc 15. In Group 1.2, it was Model

4.Model 3.Model 2.Perc 3.LAA% (-930 HU).Model

1.Perc 15.LAA% (-950 HU), as shown in Figure 5

and Table S3.

There was a significant difference between Model 4 and

LAA% (-950 HU) both in Group 1.1 and Group 1.2. The

diagnostic value of the multivariable model in diagnosing

persistent airflow limitation using different cut points is

Figure 5 The ROC curve of emphysema indexes and predicting model in diagnosing consistent airflow limitation.Notes: (A) group 1.1 (derivation group); (B) group 1.2 (internal validation group). laa% (-950 hU) and laa% (-930 hU) indicate the percentage of the lung volume occupied by low attenuation areas using the thresholds of -950 and -930 hU; Perc 3 and Perc 15 indicate percentile of the histogram of attenuation values.Abbreviations: LAA%, percentage of the lung volume occupied by low attenuation areas; Perc n, percentile of the histogram of attenuation values; ROC, receiver-operating characteristic.

shown in Table S4. Using y4.-0.7 as the criterion, the

sensitivity was 63% and 61%, and the specificity was 95%

and 97% in Group 1.1 and Group 1.2, respectively.

DiscussionIn this study, we analyzed patients’ emphysema extent on CT

scans and found its diagnostic value in identifying persistent

airflow limitation. We also developed a diagnostic criterion

for further verification.

Our results showed that almost all patients with high

FEV1/FVC had low LAA% and high Perc 15. These findings

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Cheng et al

indicated that emphysema extent (ie, LAA%, Perc n) on

CT can be a highly specific index in diagnosing persistent

airflow limitation. Moreover, Table 2 Part A reveals a posi-

tive likelihood ratio of 9.3 (Group 1.1) and 11.0 (Group 1.2)

of LAA% (-950 HU) .1.4%, 36.4 (Group 1.1) and 28.3

(Group 1.2) of LAA% (-950 HU) .3.0%, and a negative

likelihood ratio of 0.58 (Group 1.1) and 0.55 (Group 1.2) of

LAA% (-950 HU) .1.4%. It had been reported that a posi-

tive likelihood ratio .10 and a negative likelihood ratio ,0.1

were regarded as the inclusion and exclusion criteria in most

circumstances, respectively.16 Thus, we could conclude that

a patient with an LAA% (-950 HU) .1.4% should be diag-

nosed with persistent airflow limitation, and the diagnosis

was more accurate when LAA% (-950 HU) was .3.0%.

However, when LAA% (-950 HU) was ,1.4%, we

still could not exclude the possibility of persistent airflow

limitation. The sensitivity of the emphysema extent in

persistent airflow limitation diagnosis was not as satisfac-

tory as its specificity. In COPD, the narrow peripheral

airways, which resulted from inflammation and the loss of

alveolar elastic recoil force induced by emphysema (due

to parenchymal destruction), could both lead to airflow

limitation.17 Emphysema extent and airway measurements

were independent predictive factors of persistent airflow

limitation.18,19 Since COPD was a heterogenetic disease,20,21

patients with severe emphysema were supposed to suffer

from persistent airflow limitation, while the absence of

emphysema could not exclude the possibility of persistent

airflow limitation.

It had been reported that LAA% (-950 HU) and Perc 15

were widely accepted as the best indexes in CT emphysema

evaluation.22 However, the selection of the optimal threshold

was associated with the section thickness and reconstruc-

tion algorithm. Previous studies indicated that the LAA%

(-910 HU) correlated with the pathology grade of emphy-

sema on CT scan with 1 cm thickness.23 LAA% (-950 HU)

was the best index of macroscopic pathological emphysema

extent on a 1 mm thick CT image,24 and on CT images

reconstructed by 1.25, 5.0, and 10.0 mm section thickness

and 20 s algorithm, the LAA% (-960 HU), LAA% (-970

HU), and Perc 1 had close correlation with the pathology

emphysema extent.25 In our present study, the LAA% with

the threshold of -930 HU and Perc 3 had the highest AUC

in identifying persistent airflow limitation. However, there

was no significant difference in AUC between LAA% with

a threshold of -930 HU and LAA% with a threshold of -950

HU, as well as between Perc 3 and Perc 15.

Patients with COPD often suffered from other lung dis-

eases as well. We found that the coexistence of interstitial

lung disease, pneumothorax, post-thoracic surgery, and

bronchiectasis decreased the specificity of the emphysema

extent. However, the coexistence of lung infiltration, and

lung mass and nodule did not affect the specificity. This may

be due to the honeycombing in interstitial lung disease, the

area without lung texture in pneumothorax, the compensa-

tory emphysema after pulmonary lobectomy, and the dilated

airways in bronchiectasis.

In the analysis stratified by sex and age, the difference

between the patients with and without persistent airflow

limitation was more significant in males and patients aged

50–80 years. This was in line with the previous studies. It was

reported that emphysema signs on CT were more common in

men than women.26,27 Furthermore, Grydeland et al indicated

that the emphysema extent on CT increased with age in both

COPD and control groups.28 Therefore, the emphysema extent

on CT may be affected by age and sex. When LAA% (-950

HU) or Perc 15 was regarded as the only emphysema index,

the variables, including age, sex, and weight, were also inde-

pendent predictors of persistent airflow limitation. However,

if all the emphysema indexes were included, these population

characteristics were no longer independent predictors.

There were several strengths for this study. First, this was a

real-world study in China, with a relatively large sample size.

Second, our results could be inferred to the patients coexistent

with pneumonia, nodule, or mass. Third, the diagnostic values

of emphysema extent and predictor model were validated

in both internal validation and external validation groups.

However, there were also several limitations in this study.

First, some CT characteristics of COPD, including airway

remodeling and air trapping, were not included in the present

study. Second, the results of the present study were concluded

from Chinese patients in a single-center study. Therefore,

further researches in other areas and on other populations

are still needed to investigate the proper cut points and diag-

nostic values. Third, COPD is a heterogeneous disease and

persistent airflow limitation may be present without obvious

emphysema; so, our results cannot reflect COPD patients

with such characteristics. Fourth, it had been proved that CT

with ,1 mm slice thickness was more sensitive29 and higher-

resolution CT provided higher diagnostic value.30 However, in

our study, the emphysema extents were calculated from rout-

ing chest CT images (reconstructed by 5 mm thick sections

and standard algorithms). Besides, various kernels for CT

were used to evaluate the emphysema, which will affect the

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Diagnosing COPD using emphysema extent on CT

results in evaluating emphysema and bring natural limitation

to the results. Finally, the medical history including the main

symptoms and smoking status was not available, and thus, the

diagnosis of COPD was inadequate. However, based on the

present study, persistent airflow limitation can be diagnosed

based on emphysema extent on CT. Thereafter, COPD can be

diagnosed in the context of the medical history in clinics.

ConclusionThe emphysema extent on CT is a specific marker in the

diagnosis of persistent airflow limitation, which can help

with the diagnosis of COPD.

AcknowledgmentsThis study was supported by the Youth Project of Shanghai

Municipal Commission of Health and Family Planning

Research Project (No 20164Y0118), Research Foundation

of Ruijin Hospital North, Shanghai Jiao Tong University

School of Medicine (No 2015ZY04), Youth Talent Develop-

ment Program by Ruijin Hospital North (No 2017RCPY-

B04) and Shanghai Key Discipline for Respiratory Diseases

(2017ZZ02014). Ting Cheng and Yong Li share first authorship.

Author contributionsConception and design of the research: Huan Ying Wan,

Guo Chao Shi, Qi Jian Cheng, Qing Yun Li, Zi Lai Pan

and Shao Guang Huang. Acquisition of data: Ting Cheng

and Shuai Pang. Analysis and interpretation of data: Ting

Cheng and Zi Lai Pan. Statistical analysis: Ting Cheng and

Yong Li. Obtaining funding: Ting Cheng and Huan Ying

Wan. Drafting the manuscript: Ting Cheng and Yong

Li. Revision of manuscript for important intellectual content:

Huan Ying Wan and Qi Jian Cheng. All authors contributed

to data analysis, drafting and revising the article, gave final

approval of the version to be published, and agree to be

accountable for all aspects of the work.

DisclosureThe authors report no conflicts of interest in this work.

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